ALLERGEN FOCUS AND FORMALDEHYDE RELEASING PRESERVATIVES REVISITED SHARON E. JACOB, MD, ELIZABETH A. MALDONADO, AND ELISE M. HERRO, MD

with the immune system (sensitization to a chemical and then elicitation of a dermatitis with re-exposure); and that it can occur at any point in time, even to something that the patient has been using regularly for a short period of time or even intermittently for years. In certain cases, the topics of the other key players, such as irritant contact der- matitis (ICD) and contact urticaria, may be explained, as history (not patch testing) can point to these as the cor- rect diagnoses for the patient. It is im- portant to note that ICD, the most prevalent form of contact dermatitis, can at times precede or be a concomi- tant diagnosis with ACD.4,5 Unlike ACD, ICD is not immune-mediated. It occurs secondary to contact with an ir- ritating or abrasive substance. Contact urticaria (CU)(wheal and flare reac- tion), on the other hand, represents the least prevalent form of contact der- matitis. It is important to note that CU is an immune-mediated phenomenon, whose hallmark is an IgE and mast cell- llergic Contact Dermatitis (ACD) is an important disease, mediated immediate-type hypersensi- which notably affects 14.5 million Americans each year.1 The tivity reaction. We acknowledge this Aeconomic impact of this disease is high in terms of both pa- form of hypersensitivity due to the tient morbidity and loss of income, school and work, not to mention severity of the potential deleterious significant expenditures for visits to health care providers and for anaphylactic-type reactions and direct Sharon E. Jacob, MD medicaments.1 Once patch testing is performed and a culprit has the reader to key sources.6,7,8 been identified, education becomes the critical intervention to ensure In this column, we highlight ACD adherence to an avoidance regimen. With allergen avoidance, remis- and explore top relevant allergens, re- sion of the dermatitis ensues. Patients who are unable to comply with gional-based dermatitis presentations, the avoidance regimen become at risk for recurrent or sustained der- topic-based dermatitis presentations matitis or progression to a systematized presentation.2,3 In fact, edu- and clinical tips and pearls for diagnosis Elizabeth A. Maldonado cation of the patient often begins before the diagnostic patch test is and treatment. ever placed, to ensure patients have an appropriate understanding of potential outcomes and their central role in both their disease and FORMALDEHYDE AND FORMALDEHYDE- treatment. RELEASING PRESERVATIVES At the initial consultation, patients are often taught about the The mention of formaldehyde elic-

Elise M. Herro, MD pathophysiology of ACD — its delayed presentation; its relationship its visions of biopsy specimen bottles

24 JUNE 2011 | SKIN & AGING | www.skinandaging.com ALLERGEN FOCUS and medical students training on ca- medicament and personal hygiene Table 1. SOURCES OF FORMALDEHYDE OR FRPs9,14,31 davers in anatomy lab; however, there manufacturing today (Table 1). are many more potential daily en- Personal hygiene products (FRPs) counters with this chemical that often FORMALDEHYDE go unrecognized. Formaldehyde is an As with all contact allergens, the effective and inexpensive biocidal pre- more ubiquitious the usage, the more Conditioner servative that has long been used in likely it is for it then to be a top sensi- Body wash the preparation of medicaments and tizer, and formaldehyde is no excep- Hand soap cosmetic products. Early on, it was a tion. In 1939, Paul Bonnevie published frontrunner in providing cosmetics the first standard series of patch test Lotion/cream manufacturers options to comply with antigens,14 and of his 21 original aller- Baby wipes increasing safety regulations from the gens, six (including formaldehyde) are Cosmetics , Drug, and Cosmetic Act of still used in today’s patch-testing kits. 1938.9 Personal hygiene product con- In fact, unfortunately, formaldehyde is Mascara tamination had been identified as a se- a top contact allergen today for both Blush rious public health concern and adults and children, with increasing Foundation measures had to be taken to ensure the rates of sensitization.9,15,16,17 A recent safety of the consumer. For example, publication by the North American Disinfectants/Household cleaners Morse et al described six cases of sep- Contact Dermatitis Group (NACDG) Fabric softeners ticemia reported in a medical intensive reported that 9% of more than 4,400 Medicaments care unit, resulting from Klebsiella patients patch tested between 2005 and pneumoniae contamination of the 2006 were formaldehyde allergic.18 In Permethrin cream nurses’ hand cream, whose for- addition, 10.3% of the total tested pos- Topical steroids (FRPs) mulation failed to include appropriate itive to the formaldehyde-releasing Anhidrotics (FRPs) biocidal additives/preservatives.10 preservative (FRP), quaternium-15, Formaldehyde offered and contin- which was significantly higher than the Wart remedies (FRPs) ues to offer an attractive germicidal prior 2-year cycle, as well as the prior Vaccines solution for cosmetic, medicament and 10 years (1994 to 2004).18 Moreover, Inactivated Polio Vaccine32 therapeutic formulations. It also has both formaldehyde and quaternium- antiviral properties; for example, the 15 reactions were reported as being at Anthrax Vaccine Adsorbed33 Centers for Disease Control and Pre- least 93% clinically relevant, which is a Diphtheria and Tetanus Toxoids and Acellular Pertussis vention (CDC) found that an 8% con- pivotal point in patch test interpreta- Vaccine Adsorbed34 centration of formalin (a water-based tion. Clinical relevance determines to * Vaccine35 solution of formaldehyde) was enough what extent a positive allergen could to inactivate poliovirus within 10 be responsible for the patient’s clinical Food/ Maple syrup Formaldehyde offered and continues to offer an attractive Smoked germicidal solution for cosmetic, medicament and Instant crystal coffee therapeutic formulations. (through ) Clothing minutes.11 Of interest, it was this find- presentation. In order to assign rele- Permanent press finish ing that led to the development of the vance, the patch test provider and pa- Wrinkle resistant successful inactivated tient must work together to find the Corduroy (Salk vaccine) in 1952.12 Also along source of exposure and confirm its rel- those same lines, formaldehyde was evance by proving clearance of the Miscellaneous historically important in limiting the dermatitis through source avoidance. Tanned leather spread of the bubonic plague in San Since sources of formaldehyde and Plywood/particle board Francisco, when an outbreak occurred FRPs abound, from household at the turn of the 20th century.13 A cleansers to personal hygiene products Glues and adhesives concoction of lime and formaldehyde and medicaments, this can prove to be Smog was spread over Chinatown to quaran- a difficult task. Cigarette smoke tine it and reduce its spread.13 Even In order to regulate this allergen, the now, as the number of available preser- European Union had issued a Cosmet- Embalming fluid vatives has increased five fold in the ics Directive, which stated that the Tissue specimen preservation last century, formaldehyde maintains a warning label, ‘contains formaldehyde,’ *Formalin: not more than 0.1 mg/mL significant and important role in must be placed on all products contain-

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tained.9,24 Nevertheless, with time, many lergEAZE (AllergEAZE Inc., Port Table 2. FORMALDEHYDE-RELEASING FRPs were reported as contact allergens Washington, NY), while sodium hy- PRESERVATIVES (FRPS) as well, whether due to release of droxymethyl glycinate is not commer- Bromonitropropane diol (Bronopol) formaldehyde or the chemical structure cially available. Diazolidinyl (Germall II) itself.19,25 As mentioned above, the most DMDM hydantoin (Glydant) sensitizing of the FRPs, quaternium-15, PEARLS Imidazolidinyl urea (Germall) is used both commercially and industri- Dermatitis Distribution ally and is consistently ranked as a top Because formaldehyde or formalde- Quaternium-15 (Dowicil 75) contact allergen.9,25,26 In contrast, a newly hyde-releasing substances are included Tris (hydroxymethyl) nitromethane (Tris Nitro) recognized FRP is sodium hydrox- in such a wide array of products, clini- Sodium hydroxymethylglycinate (SHMG) ymethylglycinate (SHMG), and while cal distribution of a patient’s dermatitis not widely researched, it is used in many becomes critical in determining rele- ing formaldehyde or chemicals that re- child care products marketed as “nat- vant sources of exposure. For instance, lease formaldehyde if the free formalde- ural” or “organic,” as well as medica- formaldehyde exposure from textiles, hyde concentration exceeds 0.05% by ments and cosmetics.15,21 Contact allergy ie, permanent press or wrinkle-resistant weight (500 ppm).19 In addition, the to formaldehyde was recently reported clothing, can result in a dermatitis in European concentrations of FRPs are in three toddlers, with SHMG being the regions where clothing is likely to rub, limited by a maximum allowed concen- only relevant exposure to FRPs, as test- such as body folds.9 In addition, sys- tration.20 Currently, the FDA does not ing for additional releasers yielded neg- temic exposure by ingestion of con- require “pre-market” approval of cos- ative results. In addition, sustained sumables containing aspartame, which metic product labeling, and it is not improvement was noted with avoidance is metabolized to formaldehyde, for ex- permitted to advertise products in such of the personal hygiene products that ex- ample or inhalation of cigarette smoke, a way to suggest that the FDA has ap- acerbated the dermatitis, all of which can result in generalized dermatitis.9,27 proved the product.21 There are also no contained SHMG.15 regulations in place regarding concen- The mantra for ACD “treatment” is Finding Formaldehyde trations of FRPs in the United States, avoidance of the contact allergen in As mentioned above and illustrated despite studies demonstrating levels of products with which one comes into in Table 1, formaldehyde is a ubiqui- free formaldehyde in cosmetic products contact. Moreover, preventing the ini- tous chemical, included in a great vari- as low as 200 to 300 parts per million tial exposure to highly sensitizing ety of items and products. When (ppm) (0.02% to 0.03%) inducing der- chemicals — or at least rapid removal searching for formaldehyde on a prod- matitis upon short-term use on normal of the source following sensitization — uct list, one is more likely to skin.22,23 This is a possible explanation is ideal. Patch testing is the gold stan- find one of many FRPs (Table 2) listed for lower frequencies of sensitization to dard for identifying contact allergens.4,5 than the term “formaldehyde” itself. all FRPs having been reported in Eu- Screening for formaldehyde allergy can Searching for safe alternative products rope when compared to the United be done via the Thin-Layer Rapid Use can be a tedious task, but there are pro- States.20 Moreover, according to the Epicutaneous (TRUE) test, which is grams available to aid in this endeavor. United States FDA Voluntary Cosmetic commercially available and employs a Both the Contact Allergen Manage- Registration Program Database, approx- pre-made panel of allergens. The recent ment Program (CAMP), a service of- imately 20% of cosmetics and personal availability of panel 3.1 allows providers fered through the American Contact Dermatitis Society (ACDS),28 and the Because formaldehyde or formaldehyde-releasing Contact Allergen Replacement Data- substances are included in such a wide array of products, base (CARD), developed by Mayo clinical distribution of a patient’s dermatitis becomes critical Clinic,29 allow for a provider to enter a in determining relevant sources of exposure. patient’s known contact allergens, and produce a “shopping list” of products devoid of those particular chemicals. care products contain a formaldehyde- to now test for diazolidinyl urea and These programs also have the ability to releaser, with imidazolidinyl urea (7%) imidazolidinyl urea, in addition to exclude cross-reactors. being the most frequent.20 quaternium-15, which was already The development of FRPs (Table 2), available on panel 2.1. However, it is Avoiding Formaldehyde: Every Dose such as imidazolidinyl urea, was initially important to note that DMDM hydan- Counts fueled by the notion that formaldehyde toin and bromonitropropane diol As alluded to in the preface, one may would not be released in concentrations (bronopol) are currently only available be exposed to and subsequently sensi- strong enough to cause reactivity in a for comprehensive testing through tized to a contact allergen, such as formaldehyde-sensitive patient, but that Chemotechnique (Dormer Labratories formaldehyde, for days to years before antimicrobial properties would be main- Inc. Toronto, Ontario, Canada) and al- demonstrating the clinical picture of

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ACD. With each exposure, there is an gic contact urticaria from natural rubber latex 21. Cosmetic Labeling and Label Claims: increased risk of reaching a point at in healthcare and non-healthcare workers. Con- Overview. U.S. Food and Drug Administration. tact Dermatitis. 2004; 50(4): 222-224. [1screen] 2009. Available at: which the immune system meets its 7. Walsh ML, Smith VH, King CM. Type 1 and http://www.fda.gov/Cosmetics/CosmeticLa- metaphorical “threshold,” whereby type IV hypersensitivity to nickel. Australas J belingLabelClaims/default.htm. Accessed on subsequent exposures at this point can Dermatol. 2010 Nov;51(4):285-286. March 24, 2011. lead to elicitation of a cutaneous re- 8. Gimenez-Arnau A, Maurer M, De La Cuadra 22. Jordan WP Jr, Sherman WT, King SE. sponse.4,30 Just as repeated contact over J, Maibach H. Immediate contact skin reactions, Threshold responses in formaldehyde-sensitive an update of contact urticaria, contact urticaria subjects. J Am Acad Dermatol. 1979;1:44-48. time led to the immune response, re- syndrome and contact dermatitis — “a 23. Russell K, Jacob SE. Sodium hydroxymethyl- peated avoidance of the majority of ex- never ending story.” Eur J Dermatol. 2010 Sep- glycinate. Dermatitis. 2010;21(2):109-110. posures over time will be required to Oct;20(5):552-62. 24. Herbert C, Rietschel RL. Formaldehyde induce remission. Again, selecting ap- 9. Jacob SE, Steele T, Rodriguez G. M.D. Focus and formaldehyde releasers: How much avoid- propriate personal hygiene product al- on T.R.U.E. Test Allergens #21, 13, and 18: ance of cross-reacting agents is required? Con- Formaldehyde and Formaldehyde-Releasing tact Dermatitis. 2004;50(6):371-373. ternatives to include in the avoidance Preservatives. Skin & Aging. 2005;13(12):22-27. 25. Rietschel R, Fowler JF. Fisher’s Contact Der- regimen can be achieved using data- 10. Morse, LJ, Williams, HL, Grenn FP, et al. matitis. 6th ed. Hamilton, ON: BC Decker Inc; bases like those mentioned above. Septicemia due to Klebsiella pneumoniae origi- 2008:268-269. Some sources, however, require avoid- nating from a hand cream dispenser. New Engl J 26. Frosch PJ, Menné T, Lepoittevin J. Contact ance creativity, such as using a thick, Med. 1967; 277: 472-473. Dermatitis. 4th ed. New York, NY: Springer Berlin 11. Guideline for Disinfection and Sterilization Heidelberg; 2006:498. cotton throw on one’s leather couch to in Healthcare Facilities, Formaldehyde (2008). 27. Hill AM, Belsito DV. Systemic contact der- avoid the formaldehyde used in the Centers for Disease Control and Prevention matitis of the eyelids caused by formaldehyde tanning process; avoiding ingesting diet http://www.cdc.gov/hicpac/Disinfection_Ster- derived from aspartame. Contact Dermatitis. cola (aspartame); or excluding wrinkle- ilization/7_0formaldehyde.html Updated: De- 2003;49(5):258-259. resistant clothing or corduroy from cember 29, 2009 28. ACDS CAMP. American Contact Dermati- I 12. Inactivated Polio Vaccine. (1999). Polio. tis Society. 2011. Available at: http://www.con- one’s wardrobe. http://www.brown.edu/Courses/Bio_160/Proj tactderm.org/i4a/pages/index.cfm?pageid=348 ects1999/polio/vac.html. 9. Accessed March 24, 2011. Dr. Jacob, the Section Editor of Allergen 13. Chase M. The Barbary Plague. New York, 29. CARD: Contact Allergen Replacement Focus, directs the contact dermatitis clinic at NY: Random House; 2003. Database. 2011. Available at: http://www.preven- Rady Children’s hospital – UCSD in San 14. Bonnevie P. Aetiologie und Pthogenese der tice.com/card/. Accessed on March 24, 2011. Ekzemkrankheiten. Kinische Studien uber die 30. Jacob SE, Herro EM, Taylor J. Contact Der- Diego, CA. Ursachen der Ekzeme unter besonderer matitis: Diagnosis and Therapy. In Elzouki AY, Elizabeth Maldonado is an undergradu- Berucksichtigung des Diagnostischen Wertes et al, eds. Textbook of Clinical Pediatrics, Pediatric ate student at the University of California, der Ekzemproben. Busch, Copenhagen, 1939. Dermatology Section. 2nd ed. New York, NY: SD, Revelle College, Department of Bio- 15. Jacob SE, Hsu, JW. Sodium Hydroxymethyl- Springer; anticipated publication, June 2011. logical Sciences. glycinate: A Potential formaldehyde-releasing 31. Habeck M. Formaldehyde. 2010. [1 screen]. preservative in child products. Dermatitis. Eco-USA.net. Available at: http://www.eco- Dr. Herro is the Contact Dermatitis Fel- 2009;10(6):347-349. usa.net/toxics/chemicals/formaldehyde.shtml. low at Rady Children’s Hospital – UCSD 16. Zug KA, McGinley-Smith D, Warshaw EM, Accessed March 22, 2011. 2010-2011. et al. Contact allergy in children referred for 32. Poliovirus Vaccine Inactivated IPOL. U.S. patch testing: North American Contact Der- Food and Drug Administration. 2005. 1 screen. matitis Group data, 2001-2004. Arch Dermatol. Available at: 2008;144:1329-1336 http://www.fda.gov/downloads/Biologics- Disclosure: Dr. Jacob is the principal investiga- 17. Jacob SE, Steele T. Avoiding formaldehyde BloodVaccines/Vaccines/ApprovedProducts/U tor for the Smartchoice USA PREA-2 trial. allergic reactions in children. Pediatr Ann. CM133479.pdf. Accessed March 22, 2011. 2007;36:55-56. 33. BioThrax® (Anthrax Vaccine Adsorbed). References 18. Zug KA, Warshaw EM, Fowler JF, et al. U.S. Food and Drug Administration. 16 screens. Patch-test results of the North American Con- Available at: 1. Bickers DR, Lim HW, Margolis D, et al. The tact Dermatitis Group 2005–2006. Dermatitis. http://www.fda.gov/downloads/Biologics- burden of skin diseases: 2004 a joint project of 2009;20(3):149–160. BloodVaccines/BloodBloodProducts/Ap- the American Academy of Dermatology and 19. Scientific Committee on Cosmetic Products provedProducts/LicensedProductsBLAs/UCM0 the Society for Investigative Dermatology. J Am and Non-Food Products Intended for Con- 74923.pdf. Accessed March 22, 2011. Acad of Dermatol. 2006;55:490-500. sumers. Opinion concerning a clarification on 34. Diphtheria and Tetanus Toxoids and Acellu- 2. Hsu JW, Matiz C, Jacob SE. Nickel allergy: the formaldehyde and para-formaldehyde entry lar Pertussis Vaccine Adsorbed Tripedia®. U.S. localized, id, and systemic manifestations in in Directive 76/768/EEC on cosmetic products. Food and Drug Administration. 2005. 13 children. Pediatr Dermatol. 2010 Nov 18. SCCNFP/587/02, final. Adopted by the SCC- screens. Available at: 3. Salam TN, Fowler JF. Balsam-related systemic NFP during the 22nd plenary meeting of 17 http://www.fda.gov/downloads/Biologics- contact dermatitis. J Am Acad Dermatol. December 2002. Available at: BloodVaccines/Vaccines/ApprovedProducts/U 2001;45:377-381. http://ec.europa.eu/health/ph_risk/commit- CM101580.pdf. Accessed on March 22, 2011. 4. Nijhawen RI, Matiz C, Jacob SE. Contact tees/sccp/documents/out187_en.pdf (accessed 35. Havrix (Hepatitis A Vaccine). U.S. Food and dermatitis: from basics to allergodromes. Pedi- March 22, 2011). Drug Administration. 2010. 15 screens. Avail- atric Annals. 2009 Feb;38(2):99-108. 20. De Groot AC, White IR, Flyvholm M, et al. able at: http://www.fda.gov/downloads/Bio- 5. Militello G, Jacob SE, Crawford GH. Allergic Formaldehyde-releasers in cosmetics: relation- logicsBloodVaccines/Vaccines/ApprovedProduc contact dermatitis in children. CurrOpin Pediatr. ship to formaldehyde contact allergy. Contact ts/UCM224555.pdf. Accessed March 22, 2011. 2006;18:385–390. Dermatitis. 2010;62:2-17. http://www.nccam.nih.gov/health/aloevera. 6. Valks R, Conde-Salazar L, Cuevas M. Aller-

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